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Insight into the structural stability of coumestrol with human estrogen receptor alpha and beta subtypes: a combined approach involving docking and molecular dynamics simulation studies

机译：与人雌激素受体α和β亚型对Coumestror的结构稳定性见解：一种涉及对接和分子动力学模拟研究的组合方法

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Epidemiological studies suggest that dietary consumption of phytoestrogens is associated with a lower risk of breast cancer. Among phytoestrogens, coumestrol employs estrogen receptor (ER) as a target to induce apoptosis in cancer cells. Competitive binding experiments revealed a higher affinity of coumestrol for ER beta than for ER alpha. However, recent evidence demonstrates that apoptotic potential of coumestrol in breast cancer cells requires ER alpha and not ER beta. It was, therefore, pertinent to enhance our understanding of coumestrol selecting ER alpha or ER beta subtype. In the present study, we elucidated the binding mechanism of coumestrol to ER alpha and ER beta at a molecular level using molecular docking, access channel analysis and molecular dynamics (MD) simulations. The MD approach was used to determine the structural stability of coumestrol docked to ER alpha and ER beta by analysing H-bonds, interaction energy, radius of gyration, solvent-accessible surface area, root mean square deviation (RMSD), RMS fluctuation and secondary structure elements. Our results clearly suggest that coumestrol on interaction with ER beta causes an overall destabilization of Apo-ER beta structure whereas the same on interaction with ER alpha leads to strong substrate binding and an increase in Apo-ER alpha structural stability. Principal component analysis revealed higher strenuous motions of the coumestrol-ER beta complex further supporting destabilization of coumestrol-ER beta during the MD run. In conclusion, this is the first report in which in silico approaches were implemented to suggest the effect of structural stability on selective binding of coumestrol to ER alpha and not to ER beta. We expect these findings to provide significant insights into ER-based drug development particularly for receptor mediated mechanisms for breast cancer treatment.
机译：流行病学研究表明，植物雌激素的膳食消费与患乳腺癌的风险较低。在植物雌激素中，Coumestrol使用雌激素受体（ER）作为诱导癌细胞中凋亡的靶标。竞争性结合实验揭示了Coumestrol对ERβ的较高亲和力而不是ERα。然而，最近的证据表明，乳腺癌细胞中Coumestro的凋亡潜力需要ERα而不是ERβ。因此，有关提高我们对CoumestroL选择ERα或ERβ亚型的理解。在本研究中，使用分子对接，接入信道分析和分子动力学（MD）模拟，阐明了在分子水平的分子水平下对CoumeStrol对ERα和ERβ的结合机制。 MD方法用于通过分析H键，相互作用，循环，溶剂可接近的表面积，根均方偏差（RMSD），RMS波动和次级，通过分析H键，相互作用，旋转半径来确定Coumestrol对ERα和ERβ的结构稳定性。结构元素。我们的结果清楚地表明，对与ERβ的相互作用的Coumestrol导致Apo-ERβ结构的总体稳定化，而与ERα的相互作用相同，导致强基底结合和Apo-ETα结构稳定性的增加。主要成分分析显示COUMESTROL-ERβ复合物的更高剧烈运动，进一步支持MD运行期间COMESTROL-ERβ的稳定化。总之，这是第一份报告，其中在硅化方法中实施，表明结构稳定性对CoMeStrol对ERα的选择性结合而不是ERβ的影响。我们预计这些调查结果可以为eR的药物开发提供显着的见解，特别是对于受体介导的乳腺癌治疗机制。

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  • 来源
    《RSC Advances》 |2015年第99期|共18页
  • 作者

    Zafar Atif; Ahmad Sabahuddin; Naseem Imrana;

  • 作者单位

    Aligarh Muslim Univ Fac Life Sci Dept Biochem Aligarh 202002 Uttar Pradesh India;

    Jamia Millia Islamia Fac Nat Sci Dept Comp Sci New Delhi 110025 India;

    Aligarh Muslim Univ Fac Life Sci Dept Biochem Aligarh 202002 Uttar Pradesh India;

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  • 正文语种 eng
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